PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is a devastating disease usually originating from hypoxia-ischemia (H-I) before birth. It has one of the very highest indices of burden of disease because of the life-long consequences to the patient, the care-takers, and social institutions. The costs to society are huge, to the tune of $11.5 billion, not counting the loss of potential productive members of society. Prevention of a single CP patient would save almost $1.2 million, not factoring loss in productivity of the young parents of CP children. The number of affected CP patients, 800,000 in USA, and burden of disease is higher than many adult neurological diseases affecting the twilight years. Yet, there is a paucity of effective therapies for CP. The lack of progress in CP has been probably because of a lack of sufficient allocated resources, lack of a clinically relevant animal model and a lack of a systematic approach to tackle the problem. The latter two are addressed in this proposal. We will use the rabbit model of CP that develops after acute placental insufficiency at preterm gestation, based on the human disease of abruptio placentae. This H-I model is the first to reliably lead to CP, allowing us to rigorously test not only mechanistic pathways but possible therapies for CP for which there is none currently available. We have identified new novel drugs aimed at inhibiting neuronal nitric oxide synthase (nNOS) and shown that these drugs prevent CP in the rabbit when given antenatally. We have also shown that antenatal antioxidants also similarly prevent CP. With the development of a surrogate marker of MRI, we can predict which fetuses will develop postnatal motor deficits. With H-I, cell death occurs in many forms, including two forms that specifically involve oxidants, called necroptosis and ferroptosis. The main question asked in this proposal is whether the two forms of cell death triggered by oxidants, causes the development of motor deficits. The first Aim will determine which forms of cell death are critically associated specifically with motor deficits. The second Aim will determine if oxidants trigger the critical forms of cell death that lead to motor deficits. The underlying biochemical mechanisms will be studied utilizing the identification of fetuses destined to get postnatal hypertonia and studying entire brain, brain regions and cell suspensions. New innovations proposed are the systemic integration of MRI as a surrogate marker with flow cytometry techniques, electron microscopy, electron paramagnetic spectroscopy and high performance liquid chromatography into the unique animal model to probe the biochemical basis of two forms of cell death. These studies will elucidate the early events around critical cell death that cause motor deficits. The clinical importance is that the proposed studies provides the mechanistic understanding for the systematic development of much-needed therapies for CP, and thus expedites the clinical application of these therapies.